Physiological and molecular responses of the copepods Acartia clausi and Acartia tonsa to nickel nanoparticles and nickel chloride.

Nickel compounds in dissolved form or as nanoparticles may affect planktonic invertebrates in marine ecosystems. Here, we assessed the physiological (naupliar mortality, egg production, egg hatching success) and molecular (quantitative gene expression) responses of the crustacean copepods Acartia clausi (indigenous Mediterranean species) and Acartia tonsa (model organism in ecotoxicology), to nickel nanoparticles (NiNPs) and nickel chloride (NiCl2), over time. We also measured NPs size and the temporal release of Ni ions in aqueous solution, through dynamic light scattering (DLS) and inductively coupled plasma-mass spectrometry (ICP-MS), respectively. Nauplii of A. clausi were highly vulnerable to NiCl2 in the 48 h acute test, with an EC50 in the range of Ni concentrations measured in polluted waters. Females of both species exhibited a decreased egg production and hatching success after the 4-day exposure to NiNPs. Molecular responses in A. clausi incubated in NiNPs and NiCl2 showed a stronger up- or down-regulation, compared to A. tonsa, of genes associated with detoxification (phospholipid-hydroperoxide glutathione peroxidase, glutathione-S-transferase sigma), oxidative stress (superoxide dismutase), nervous system functioning (acetylcholinesterase), and oogenesis (vitellogenin). In conclusion, new information was here obtained on the effects of different forms of nickel on physiological and molecular responses of A. clausi, that could help to identify biomarker genes of exposure to be used as early-warning indicators. Our results also highlighted the need of employing indigenous copepod species to better evaluate the ecotoxicological impact of pollutants in different geographical area.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

A Novel Intraoperative Ultrasound Probe for Transsphenoidal Surgery: First-in-human study.

Background. Ultrasound has been explored as an alternative, less bulky, less time-consuming and less expensive means of intraoperative imaging in pituitary surgery. However, its use has been limited by the size of its probes relative to the transsphenoidal corridor. We developed a novel prototype that is more slender than previously reported forward-viewing probes and, in this report, we assess its feasibility and safety in an initial patient cohort. Method. The probe was integrated into the transsphenoidal approach in patients with pituitary adenoma, following a single-centre prospective proof of concept study design, as defined by the Innovation, Development, Exploration, Assessment and Long-Term Study (IDEAL) guidelines for assessing innovation in surgery (IDEAL stage 1 - Idea phase). Results. The probe was employed in 5 cases, and its ability to be used alongside the standard surgical equipment was demonstrated in each case. No adverse events were encountered. The average surgical time was 20 minutes longer than that of 30 contemporaneous cases operated without intraoperative ultrasound. Conclusion. We demonstrate the safety and feasibility of our novel ultrasound probe during transsphenoidal procedures to the pituitary fossa, and, as a next step, plan to integrate the device into a surgical navigation system (IDEAL Stage 2a - Development phase).

De novo transcriptome assembly and differential gene expression analysis of the calanoid copepod Acartia tonsa exposed to nickel nanoparticles.

The calanoid copepod Acartia tonsa is a reference species in standardized ecotoxicology bioassay. Despite this interest, there is a lack of knowledge on molecular responses of A. tonsa to contaminants. We generated a de novo assembled transcriptome of A. tonsa exposed 4 days to 8.5 and 17 mg/L nickel nanoparticles (NiNPs), which have been shown to reduce egg hatching success and larval survival but had no effects on the adults. Aims of our study were to 1) improve the knowledge on the molecular responses of A. tonsa copepod and 2) increase the genomic resources of this copepod for further identification of potential biomarkers of NP exposure. The de novo assembled transcriptome of A. tonsa consisted of 53,619 unigenes, which were further annotated to nr, GO, KOG and KEGG databases. In particular, most unigenes were assigned to Metabolic and Cellular processes (34-45%) GO terms, and to Human disease (28%) and Organismal systems (23%) KEGG categories. Comparison among treatments showed that 373 unigenes were differentially expressed in A. tonsa exposed to NiNPs at 8.5 and 17 mg/L, with respect to control. Most of these genes were downregulated and took part in ribosome biogenesis, translation and protein turnover, thus suggesting that NiNPs could affect the copepod ribosome synthesis machinery and functioning. Overall, our study highlights the potential of toxicogenomic approach in gaining more mechanistic and functional information about the mode of action of emerging compounds on marine organisms, for biomarker discovering in crustaceans.

A novel flexible hyper-redundant surgical robot: prototype evaluation using a single incision flexible access pelvic application as a clinical exemplar.

INTRODUCTION: The flexible endoscope is increasingly being considered as a surgical tool to enable innovative natural orifice or flexible access techniques. These experiences have exposed unique advantages but also significant challenges. Major current technical drawbacks in this setting relate to uncontrolled flexibility, inaccurate sustained target localization, unreliable navigation and overall platform instability. In striving to address existing technical limitations, this paper introduces a novel flexible hyper-redundant surgical robot and evaluates its clinical potential using a focused clinical application. METHOD: To assess utility of the device within tight confines of the human pelvis or peritoneal cavity, detailed laboratory workspace analysis experiments were undertaken using a computer-simulated model that incorporated anatomical data obtained via pelvic magnetic resonance images of eight women. Ten participants executed ninety usability and reliability trials on an ex vivo simulator, before the robot was repeatedly trialled in an in vivo porcine model. RESULTS: The robot demonstrated capability of targeting >90 % of the anatomic region of interest. All 90 user trials were successfully performed without interruption or malfunction. Significant improvements in performance, time and motion were observed between first and last sets of trials (p = 0.001). In vivo feasibility testing affirmed robustness of the device when deployed within the physiological demands of a live scale appropriate model. CONCLUSION: Technologically advanced flexible operative platforms are needed to fulfil aspirations for an introductory era of flexible access surgery. This prototype is proposed as a potential future platform for robot-assisted flexible endoscopic surgery. Encouraging pre-clinical feasibility results are demonstrated for diagnostic and therapeutic applications within the pelvis.

Emerging robotic platforms for minimally invasive surgery.

Recent technological advances in surgery have resulted in the development of a range of new techniques that have reduced patient trauma, shortened hospitalization, and improved diagnostic accuracy and therapeutic outcome. Despite the many appreciated benefits of minimally invasive surgery (MIS) compared to traditional approaches, there are still significant drawbacks associated with conventional MIS including poor instrument control and ergonomics caused by rigid instrumentation and its associated fulcrum effect. The use of robot assistance has helped to realize the full potential of MIS with improved consistency, safety and accuracy. The development of articulated, precision tools to enhance the surgeon's dexterity has evolved in parallel with advances in imaging and human-robot interaction. This has improved hand-eye coordination and manual precision down to micron scales, with the capability of navigating through complex anatomical pathways. In this review paper, clinical requirements and technical challenges related to the design of robotic platforms for flexible access surgery are discussed. Allied technical approaches and engineering challenges related to instrument design, intraoperative guidance, and intelligent human-robot interaction are reviewed. We also highlight emerging designs and research opportunities in the field by assessing the current limitations and open technical challenges for the wider clinical uptake of robotic platforms in MIS.

Dimensionality Reduction in Controlling Articulated Snake Robot for Endoscopy Under Dynamic Active Constraints.

This paper presents a real-time control framework for a snake robot with hyper-kinematic redundancy under dynamic active constraints for minimally invasive surgery. A proximity query (PQ) formulation is proposed to compute the deviation of the robot motion from predefined anatomical constraints. The proposed method is generic and can be applied to any snake robot represented as a set of control vertices. The proposed PQ formulation is implemented on a graphic processing unit, allowing for fast updates over 1 kHz. We also demonstrate that the robot joint space can be characterized into lower dimensional space for smooth articulation. A novel motion parameterization scheme in polar coordinates is proposed to describe the transition of motion, thus allowing for direct manual control of the robot using standard interface devices with limited degrees of freedom. Under the proposed framework, the correct alignment between the visual and motor axes is ensured, and haptic guidance is provided to prevent excessive force applied to the tissue by the robot body. A resistance force is further incorporated to enhance smooth pursuit movement matched to the dynamic response and actuation limit of the robot. To demonstrate the practical value of the proposed platform with enhanced ergonomic control, detailed quantitative performance evaluation was conducted on a group of subjects performing simulated intraluminal and intracavity endoscopic tasks.

Robot-assisted transvaginal peritoneoscopy using confocal endomicroscopy: a feasibility study in a porcine model.

BACKGROUND: Optical biopsy methods such as probe-based confocal laser endomicroscopy (pCLE) provide useful intraoperative real-time information, especially during minimally invasive surgery with flexible endoscopic or robotic platforms. By translating the probe at constant pressure across the target tissue, undistorted "mosaics" can be produced. However, this poses ergonomic challenges with a conventional flexible endoscope. METHODS: A 100 µm confocal depth pCLE probe was integrated into a previously described seven degrees-of-freedom articulated endoscopic robot. After estimating the average workspace created by a female pneumoperitoneum, the accessibility of the peritoneal cavity by the device for robot-assisted pCLE peritoneoscopy was calculated. To demonstrate its in vivo feasibility, the robot was inserted transvaginally in a pig, under laparoscopic vision. Optical biopsy was performed of several targets within the peritoneal cavity. RESULTS: The workspace analysis calculated that 88 % of the surface of an estimated average female pneumoperitoneum could be contacted by the probe using the robot transvaginally. In vivo, the robot was manoeuvred to provide views of all abdominal and pelvic organs. At each target there was robotic acquisition of still pCLE images, and slowly translating images for the construction of increased field-of-view mosaics up to 2 mm in length. Optical biopsies took 1-2 min per target, and at 3.5 µm lateral resolution, the mosaic images showed characteristic features of anterior abdominal wall, liver, and spleen. CONCLUSION: In the porcine model, the robotically actuated method of performing peritoneoscopy and pCLE mosaicked optical biopsy is safe and provides a consistent means of acquiring near-histological grade images of submesothelial tissue. Clinical translation is likely to provide sufficient accessibility of the peritoneal cavity.

Control of articulated snake robot under dynamic active constraints.

Flexible, ergonomically enhanced surgical robots have important applications to transluminal endoscopic surgery, for which path-following and dynamic shape conformance are essential. In this paper, kinematic control of a snake robot for motion stabilisation under dynamic active constraints is addressed. The main objective is to enable the robot to track the visual target accurately and steadily on deforming tissue whilst conforming to pre-defined anatomical constraints. The motion tracking can also be augmented with manual control. By taking into account the physical limits in terms of maximum frequency response of the system (manifested as a delay between the input of the manipulator and the movement of the end-effector), we show the importance of visual-motor synchronisation for performing accurate smooth pursuit movements. Detailed user experiments are performed to demonstrate the practical value of the proposed control mechanism.

From medical images to minimally invasive intervention: Computer assistance for robotic surgery.

Minimally invasive surgery has been established as an important way forward in surgery for reducing patient trauma and hospitalization with improved prognosis. The introduction of robotic assistance enhances the manual dexterity and accuracy of instrument manipulation. Further development of the field in using pre- and intra-operative imaging guidance requires the integration of the general anatomy of the patient with clear pathologic indications and geometrical information for preoperative planning and intra-operative manipulation. It also requires effective visualization and the recreation of haptic and tactile sensing with dynamic active constraints to improve consistency and safety of the surgical procedures. This paper describes key technical considerations of tissue deformation tracking, 3D reconstruction, subject-specific modeling, image guidance and augmented reality for robotic assisted minimally invasive surgery. It highlights the importance of adapting preoperative surgical planning according to intra-operative data and illustrates how dynamic information such as tissue deformation can be incorporated into the surgical navigation framework. Some of the recent trends are discussed in terms of instrument design and the usage of dynamic active constraints and human-robot perceptual docking for robotic assisted minimally invasive surgery.

Perceptually Docked Control Environment for Multiple Microbots: Application to the Gastric Wall Biopsy.

This paper presents a human-robot interface with perceptual docking to allow for the control of multiple microbots. The aim is to demonstrate that real-time eye tracking can be used for empowering robots with human vision by using knowledge acquired in situ. Several micro-robots can be directly controlled through a combination of manual and eye control. The novel control environment is demonstrated on a virtual biopsy of gastric lesion through an endoluminal approach. Twenty-one subjects were recruited to test the control environment. Statistical analysis was conducted on the completion time of the task using the keyboard control and the proposed eye tracking framework. System integration with the concept of perceptual docking framework demonstrated statistically significant improvement of task execution.